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Role of GTPases and GTPase regulatory proteins in oncogenesis
1Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Abstract:
The GTPases comprise a superfamily of GTP-binding proteins with intrinsic GTPase activity. Some members of this family representing either heterotrimeric or small G-proteins are involved in the transmission of mitogenic signals. Mutations that lead to constitutively activated G-proteins have been shown to contribute to malignant transformation. These genes represent, therefore, putative oncogenes. Examples are the gsp and gip2 oncogenes, encoding GTPase deficient alpha-subnits of Gs or Gi-2 proteins. Representatives from the family of small G-proteins are the products of the Harvey-, Kirsten- or N-ras oncogenes. These oncogenes, which are frequently expressed in human malignancies, code for proteins (p21ras) that are locked in the activated GTP-bound state because their GTPase is refractory to the ras-specific GTPase activating protein (GAP). In other cases p21ras-GTP levels have been found to be elevated as a result of an increase in GDP/GTP exchange rate. In neurofibromatosis v. Recklinghausen, a mutated gene (NF1) is detectable. The protein encoded by NF1 contains a GAP homology region, binds p21ras-GTP, and stimulates the hydrolysis of p21ras-bound GTP. Both ras-GAP (p120 GAP) and NF1-GAP are inhibited by acidic lipids. Elevated levels of these lipids may exert growth-stimulatory or perhaps tumor-promoting activity by increasing p21ras GTP. The function of transforming p21ras is under control of tumor suppressor genes. Putative suppressor genes isolated from revertants from ras-transformed cells include rsp-1 and the ras recision gene (rrg). Experimentally, an overexpression of Rap 1A/Krev-1 is able to antagonize transformation by p21ras. This mechanism also may be relevant under normal conditions. p53 also is capable of inhibiting transforming p21ras. It is postulated that p105-RB exerts a similar anti-ras effect. The mechanism by which retinoic acid suppresses transformation by ras is discussed. Current strategies for a pharmacological interference of p21ras function are described.
Insights
Mutations in GTPases, like ras oncogenes, can cause cancer by locking proteins in an active state. Tumor suppressor genes and other factors can counteract this transforming activity.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- GTPases are critical for cell signaling, with mutations linked to cancer.
- Specific GTPases, such as ras proteins, are frequently implicated in human malignancies.
- Dysregulation of GTPase activity can lead to uncontrolled cell growth and malignant transformation.
Purpose of the Study:
- To review the role of GTPases, particularly ras proteins, in cancer development.
- To explore the mechanisms by which GTPase mutations lead to oncogenesis.
- To discuss regulatory mechanisms and potential therapeutic strategies targeting GTPases.
Main Methods:
- Review of existing literature on GTPases, oncogenes, and tumor suppressor genes.
- Analysis of molecular mechanisms underlying GTPase-mediated cell signaling and transformation.
- Discussion of pharmacological interventions for GTPase-related cancers.
Main Results:
- Mutated GTPases (oncogenes) like ras can become constitutively active, driving malignant transformation.
- GTPase activating proteins (GAPs) regulate GTPase activity, and their dysfunction contributes to cancer.
- Tumor suppressor genes (e.g., NF1, p53, RB) and other factors can inhibit oncogenic GTPase function.
Conclusions:
- GTPase dysregulation is a key factor in cancer initiation and progression.
- Understanding these pathways offers targets for novel cancer therapies.
- Interference with oncogenic GTPase function is a promising therapeutic strategy.